Deletion of newly described pro-survival molecule Pellino-1 increases oxidative stress, downregulates cIAP2/NF-κB cell survival pathway, reduces angiogenic response, and thereby aggravates tissue function in mouse ischemic models.

INTRODUCTION: In the present study, we aimed to explore the functional role of Pellino-1 (Peli1) in inducing neovascularization after myocardial infarction (MI) and hindlimb ischemia (HLI) using Peli1 global knockout mice (Peli1-/-). Recently we have shown that Peli1, an E3 ubiquitin ligase, induce angiogenesis and improve survivability, with decreased necrosis of ischemic skin flaps. METHODS: Peli1fl/fl and Peli1-/- mice were subjected to either permanent ligation of the left anterior descending coronary artery (LAD) or sham surgery (S). Tissues from the left ventricular risk area were collected at different time points post-MI. In addition, Peli1fl/fl and Peli1-/- mice were also subjected to permanent ligation of the right femoral artery followed by motor function scores, Doppler analysis for blood perfusion and immunohistochemical analysis. RESULTS: Global Peli1 knockout exacerbated myocardial dysfunction, 30 and 60 days after MI compared to wild type (WT) mice as measured by echocardiogram. In addition, Peli1-/- mice also showed decreased motor function scores and perfusion ratios compared with Peli1fl/fl mice 28 days after the induction of HLI. The use of Peli1 in adenoviral gene therapy following HLI in CD1 mice improved the perfusion ratio at 28 days compared to Ad.LacZ-injected mice. CONCLUSION: These results suggest new insights into the protective role of Peli1 on ischemic tissues and its influence on survival signaling.

Overexpression of Thioredoxin1 enhances functional recovery in a mouse model of hind limb ischemia.

BACKGROUND: There is keen interest in finding nonsurgical treatments for peripheral vascular disease (PVD). Previously, we demonstrated that selective activation of Thioredoxin1 (Trx1), a 12-kDa cytosolic protein, initiates redox-dependent signaling and promotes neovascularization after ischemic heart disease. Therefore, Trx1 might possess immense potential to not only treat murine hind limb ischemia (HLI) through effective angiogenesis but also provide PVD patients with nonsurgical therapy to enhance neovascularization and improve blood perfusion. METHODS: To determine whether activation of Trx1 increases blood perfusion in HLI, two different strategies were used-gene therapy and transgenic model system. In adenoviral-mediated gene therapy, 8- to 12-wk-old mice were divided into two groups: (1) control Adeno-LacZ (Ad-LacZ) and (2) Adeno-Thiroedoxin1 (Ad-Trx1). The mice underwent surgical intervention to induce right HLI followed by injection with Ad-LacZ or Ad-Trx1, respectively. In the second strategy, we used wild-type and transgenic mice overexpressing Trx1 (Trx1Tg/+). All the animals underwent Doppler imaging for the assessment of limb perfusion followed by immunohistochemistry and Western blot analysis. RESULTS: Significant increases in perfusion ratio were observed in all the Trx1 overexpressed groups compared with their corresponding controls. Expressions of heme oxygenase-1, vascular endothelial growth factor, and the vascular endothelial growth factor receptors Flk-1 and Flt-1 were increased in Trx1 overexpressed mice compared with their respective controls. Blood perfusion in the ischemic limb gradually improved and significantly recovered in Trx1Tg/+ and Ad-Trx1 groups compared with their corresponding controls. The capillary and arteriolar density in the ischemic zone were found to be higher in Trx1Tg/+ group compared with wild type. CONCLUSIONS: The overall outcomes of our study demonstrate that Trx1 enhances blood perfusion and increases angiogenic protein expression in a rodent HLI model. These results suggest that Trx1 is a potential target for clinical trials and drug therapy for the treatment of PVD.

Deletion of prolyl hydroxylase domain proteins (PHD1, PHD3) stabilizes hypoxia inducible factor-1 alpha, promotes neovascularization, and improves perfusion in a murine model of hind-limb ischemia.

BACKGROUND: There is an emerging focus on investigating innovative therapeutic molecules that can potentially augment neovascularization in order to treat peripheral arterial disease (PAD). Although prolyl hydroxylase domain proteins 1 and 3 (PHD1 and PHD3) may modulate angiogenesis via regulation of hypoxia inducible factor-1α (HIF-1α), there has been no study directly addressing their roles in ischemia-induced vascular growth. We hypothesize that PHD1(-/-) or PHD3(-/-) deficiency might promote angiogenesis in the murine hind-limb ischemia (HLI) model. STUDY DESIGN: Wild type (WT), PHD1(-/-) and PHD3(-/-) male mice aged 8-12weeks underwent right femoral artery ligation. Post-procedurally, motor function assessment and laser Doppler imaging were periodically performed. The mice were euthanized after 28days and muscles were harvested. Immunohistochemical analysis was performed to determine the extent of angiogenesis by measuring capillary and arteriolar density. VEGF expression was quantified by enzyme-linked immunosorbent assay (ELISA). Bcl-2 and HIF-1α were analyzed by immunofluorescence. Fibrosis was measured by picrosirius red staining. RESULTS: PHD1(-/-) and PHD3(-/-) mice showed significantly improved recovery of perfusion and motor function score when compared to WT after femoral artery ligation. These mice also exhibited increased capillary and arteriolar density, capillary/myocyte ratio along with decreased fibrosis compared to WT. VEGF, Bcl-2 and HIF-1α expression increased in PHD1(-/-) and PHD3(-/-) mice compared to WT. CONCLUSIONS: Taken together these results suggest that PHD1 and PHD3 deletions promote angiogenesis in ischemia-injured tissue, and may present a promising therapeutic strategy in treating PAD.

Tick-borne trauma: an unusual presentation of anaplasmosis.

INTRODUCTION: Tick-borne diseases present a special problem in Connecticut and the Northeastern United States. The tick species Ixodes scapularis known for Lyme disease may also infect humans with anaplasmosis, while other tick species [Amblyomma spp.] may transmit ehrlichiosis. These illnesses may present in various ways depending on the virulence of the organism and variable host factors. CASE PRESENTATION: Our patient presented as a motor vehicle trauma presumably from encephalopathy secondary to anaplasmosis. Unusual features of the patient's case led to the causative diagnosis on peripheral blood smear examination. CONCLUSION: Tick-borne diseases are endemic in Connecticut. The astute clinician should maintain a healthy vigilance for these illnesses. Although our patient presented as a trauma, the presumed precipitating disease could have been treated. Physician awareness and patient education may lessen the impact of these diseases.

Computed tomographic modeling before and after treatment for posttraumatic empyema: early decortication is superior to catheter drainage.

BACKGROUND: Posttraumatic empyema is relatively unusual. There are little data comparing the results of various interventions, and no data that have documented the restoration of lung volumes. METHODS: We compared patients with posttraumatic empyema who were treated with catheter drainage or decortication. Computed tomographic scans of the chest were obtained before and after treatment, and computed tomographic modeling was used to determine the change in lung volumes after each intervention. RESULTS: From 2006 to 2010 there were 478 patients admitted after sustaining chest trauma and 25 (5%) developed an empyema. The definitive treatment was decortication in 15 patients (60%) and chest tube or catheter drainage in 10 (40%). Four patients (16%) initially treated with chest tubes later required decortication. The overall complication rate was 33% for decortication and 100% for catheters. There was no significant difference in days of mechanical ventilation (catheter-median 0, SD±13 days; decortication-median 10, SD±12 days; p=0.6), total length of stay (catheter-median 15, SD±36 days; decortication-median 27, SD±17 days; p=0.9), and intensive care unit days (catheter-median 6, SD±19 days; decortication-median 15, SD±17 days; p=0.5). After chest tube drainage, the lung volume increased on average by 751 cubic centimeters (range, 99 to 1,982 cc). After decortication, the lung volume increased on average by 1,519 cc (range, 616 to 2,916, p=0.02). CONCLUSIONS: Decortication for posttraumatic empyema results in higher postoperative lung volumes than catheter drainage and has a lower complication rate. Decortication is more effective in restoring full pulmonary capacity in the treatment of posttraumatic empyema.